This project, in part, represents an extension of work previously reported as Project Numbers Z01 DK69037, Z01 DK069097 and Z01 DK069000. It also reports on continuation of work previously reported under Project Numbers DK069036-23, DK069063-17, and DK069100-06. All work related to diabetic nephropathy, with the exception of the genetics of diabetic nephropathy and our participation in multicenter clinical trials, is now reported under this single project. In the last year, we continued to work with an international consortium known as the CKD Prognosis Consortium that is examining the prognostic implications of low estimated glomerular filtration rate and elevated albuminuria for mortality, kidney disease, and cardiovascular outcomes. Using data from numerous cohorts, the Consortium reported that a kidney failure risk equation previously validated in two Canadian cohorts is also valid worldwide, and accurately predicts risk of progression from CKD stages 3-5 to kidney failure in a diverse group of patients. In regions outside North America, a calibration factor is recommended. In two papers published in Kidney International, we demonstrated that elevated serum concentrations of tumor necrosis factor receptors 1 and 2 were associated with an increased risk of end-stage renal disease in Pima Indians with type 2 diabetes after accounting for traditional risk factors, including measured glomerular filtration rate and albuminuria. We went on to demonstrate that specific structural lesions were strongly associated with serum concentrations of these receptors. The strongest relationships were with increased mesangial fractional volume and loss of endothelial cell fenestrations. These findings suggest that elevated circulating concentrations of the tumor necrosis factor receptors 1 and 2 may be involved in the pathogenesis of early glomerular lesions in diabetic nephropathy. We published several papers with the NIDDK Biomarkers Consortium in the past year, including one which found that increased urinary concentration of NGAL and reduced urinary concentration of LFABP were associated with important health outcomes, including end-stage renal disease and death, in Pima Indians with type 2 diabetes. We also found that elevated urinary concentrations of MCP-1 measured before clinical findings of diabetic nephropathy in women with type 1 diabetes was associated with changes in kidney interstitial volume. Our work in the biomarkers consortium taught us much about the potential errors associated with biomarkers research, and we published a paper in the Clinical Journal of the American Society of Nephrology in which we described a variety of quality control issues we encountered during our work with the Consortium. We continue to contribute to the development of national and international guidelines for the management of kidney disease. This year, we published a paper in Kidney International in which we described several controversies in diabetic nephropathy research that need to be addressed. We also updated a joint statement from the American Heart Association and the American Diabetes Association that describes prevention of cardiovascular disease in persons with type 2 diabetes. This update was published in Circulation and in Diabetes Care.